Non-myeloablative approaches to hematopoietic cell transplantation (HCT) can potentially harness an immunotherapeutic graft-versus-tumor benefit while avoiding some of the severe toxicities associated with conventional, myeloablative HCT. Several clinical studies of non-myeloablative HCT have revealed a new and surprising phenomenon wherein loss of donor chimerism can sometimes be associated with sustained tumor regressions, even of advanced hematologic malignancies. We have developed a murine model in which to assess the mechanism of this phenomenon. We have demonstrated that alloresponses against donor antigens (either in association with spontaneous graft rejection or induced by infusion of non-tolerant host-type lymphocytes) lead to significant anti-tumor responses against recipient myeloid or lymphoid tumors. We now propose to optimize and determine the mechanisms underlying this phenomenon, which suggests a new strategy for achieving anti-tumor effects without augmenting the risk of GVHD. Specifically, we aim: 1) To determine the source and phenotype of cells mediating anti-tumor effects following recipient lymphocyte infusions (RLI) or spontaneous loss of chimerism; 2) To address the hypothesis that indirect presentation of alloantigens by recipient APC leads to the generation of tumor antigen-specific effector CTL and cytokine-producing cells in chimeras receiving RLI; 3) To utilize a TCR transgenic/model tumor antigen system to directly assess the hypothesis that RLI leads to a loss of tolerance among CD4+ and CD8+ cells that recognize tumor antigens; 4) To determine the mechanism by which IFN-gamma mediates anti-tumor effects in RLI recipients; 5) To evaluate strategies for optimizing the anti-tumor effect of RLI. Results of these studies will lead toward an understanding of the immunological events underlying the clinical phenomenon of tumor regression associated with rejection of donor marrow. Moreover, they will advance the development of a potential new strategy for achieving anti-tumor effects that is not associated with a risk of graft-versus-host disease, the major complication that currently limits the clinical success of non-myeloablative HCT.